Elsevier

The Lancet

Volume 382, Issue 9896, 14–20 September 2013, Pages 951-962
The Lancet

Articles
Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis

https://doi.org/10.1016/S0140-6736(13)60733-3Get rights and content

Summary

Background

The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.

Methods

We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation.

Findings

We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73–1·03; amisulpride 0·66, 0·53–0·78; olanzapine 0·59, 0·53–0·65; risperidone 0·56, 0·50–0·63; paliperidone 0·50, 0·39–0·60; zotepine 0·49, 0·31–0·66; haloperidol 0·45, 0·39–0·51; quetiapine 0·44, 0·35–0·52; aripiprazole 0·43, 0·34–0·52; sertindole 0·39, 0·26–0·52; ziprasidone 0·39, 0·30–0·49; chlorpromazine 0·38, 0·23–0·54; asenapine 0·38, 0·25–0·51; lurasidone 0·33, 0·21–0·45; and iloperidone 0·33, 0·22–0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.

Interpretation

Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines.

Funding

None.

Introduction

Schizophrenia is a debilitating disease, ranked among the top 20 causes of disability worldwide.1 The question of which antipsychotic drug should be preferred for treatment of the disease is controversial, largely because of the substantial costs of second-generation antipsychotic drugs (estimated US$14·5 billion globally in 2014).2 New antipsychotic drugs such as asenapine, iloperidone, lurasidone, and paliperidone continue to be marketed, but as earlier second-generation drugs come off patent, an important question is whether the newest drugs are cost effective. Previous conventional pairwise meta-analyses3, 4, 5 could not generate clear hierarchies for the efficacy and side-effects of available treatments, because many antipsychotic drugs have not been compared head to head,6 and because such analyses could not integrate all the evidence from several comparators. As such, any attempt to create such hierarchies was necessarily impressionistic, and guidelines urgently need accurate information to address this question. We aimed to compare the two prototypal first-generation (haloperidol and chlorpromazine) and 13 second-generation antipsychotic drugs when used in patients with schizophrenia. Our intention was to provide evidence-based hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.

Section snippets

Participants and interventions

We did a multiple-treatments meta-analysis to compare 15 antipsychotic drugs for schizophrenia. Multiple-treatments meta-analysis allows the integration of direct and indirect comparisons of antipsychotic drugs (ie, how two or more drugs compare with a common comparator). We followed the same approach as was used in two previous multiple-treatments meta-analyses, of major depressive disorder7 and bipolar mania.8

Our analysis included studies of people with schizophrenia or related disorders

Results

212 studies reported between October, 1955, and September, 2012, with 43 049 participants, were included in the analysis (details of included studies are shown in appendix pp 41–65; PRISMA41 flowcharts are shown in appendix pp 70–76). The mean duration of illness was 12·4 years (SD 6·6) and the mean age of trial participants was 38·4 years (SD 6·9). Nine studies exclusively examined first-episode patients. In terms of study quality, the reports often did not provide details about randomisation

Discussion

Our multiple-treatments meta-analysis provides evidence-based hierarchies for the efficacy and tolerability of antipsychotic drugs, overcoming the major limitation of conventional pairwise meta-analyses.3, 4, 21 Results for our primary outcome challenge the dogma that the efficacy of all antipsychotic drugs is the same. This notion originated from an influential narrative review published in 1969,45 but it has not been scientifically addressed since.

The efficacy hierarchy generated by our

Acknowledgments

We thank Julian Higgins for his work on the protocol; Anna Chaimani for assistance with the statistical analysis; and Claudia Leucht, Maximilian Huhn, Markus Dold, Haoyin Cao, and Magdolna Tardy for their help in preparing the report. For sending us information about their studies, we thank Ebrahim Abdolahian, Christian Barnas, Michael Berk, Warrick Brewer, Roberto Cavallaro, Eva Ceskova, Mark Corrigan, Jair de Jesus Mari, Wolfgang Fleischhacker, Kotaro Hatta, Tzung-Jeng Hwang, Peter Jones,

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